Claude-Agnès Reynaud and Jean-Claude Weill got a PhD in molecular biology at the Institute Jacques Monod (Paris) in the team of K. Scherrer in 1981 and 1980. They then studied the generation of the antibody repertoire using the chicken model and discovered gene conversion as a generator of antibody diversity. They moved to the Basel Institute in 1987 where they further develop repertoire studies in the sheep model. In 1991, JCW was appointed Professor of Immunology at the Necker hospital, and CAR Director of Research at CNRS and started to study the development of the B cell compartment in mice and humans. Since 2010, JCW is Professor Emeritus.

Awards : CAR got the Silver Medal from CNRS (1991) and JCW is a member of the French Academy of Sciences (2011). They are both EMBO members and received an ERC Advanced grant, in 2010 and 2016, respectively

Focus

Understanding the functional diversity of B cell memory and effector subsets during immune responses in both mice and humans, as well as in human autoimmune diseases mediated by pathogenic antibodies.

Introduction

Most vaccines are based on antibodies and thus on the B cell arm of the immune system, but one still does not have a clear picture of the cellular and molecular basis of B cell memory. We have recently proposed, using a fate mapping mouse model, the concept of “multi-layered B cell memory response”, which implies that there are different memory B cell subsets with different effector functions engaged in a recall response. Nevertheless, the behavior of each B cell memory subset seems to vary depending on the model studied, i.e. on factors such as the type of antigen and adjuvant used and the timing of successive immune challenges. As an additional complexity, the human memory B cell compartment appears very different from the one of rodents in term of subsets and phenotypes. Improved vaccination strategies will therefore depend on a better understanding of what are the B cell subsets involved during responses against induced (vaccines) or natural (infection) antigenic challenges. Our project aims at addressing several of these questions and is developed along five axes.

Research objectives

Long-term memory in humans: deciphering the molecular basis of life-long persistence.Based on the study of memory B cells against smallpox, we wish to determine whether long-lived memory B cells present a specific transcriptional program and a distinct cellular homeostasis.

Marginal zone and IgM memory B cells in humans: two subsets with distinct effector functions and differentation/activation pathways?
Our recent data suggest that IgM memory and marginal zone B cells represent two different subsets with distinct Ig repertoires. We will study their differential mobilization in an anti-pneumococcal response, their expression/activation profile and their ontogeny in a humanized mouse model.

Immune thrombocytopenia (ITP), as a model for auto-immune diseases mediated by antibodies.
We will take advantage of the therapeutic setting of splenectomy performed after B-cell depletion (rituximab) treatment failure to analyze, during relapse of the disease, what B-cell specificities (self-antigens, infectious agents) emerge in the various B cell subsets engaged in the active splenic immune response and whether it could give insight into the causes of the autoimmune process.

An inducible fate-mapping mouse model to follow germinal center-derived TFH and memory B cells.
An inducible Cre-ERT2 mouse model based on Bcl6 gene expression will allow us to follow how memory B and TFH cells persist and cooperate during a recall response, and whether TFH cells represent a stable lineage or can adopt multiple fates upon further challenges.

The human ICF syndrome (Immunodeficiency, Centromeric instability and Facial dismorphism): can we get insight into the memory vs. plasma cell lineage choice taking place in germinal centers through the study of mouse models of this syndrome, a genetic disease caused by the inactivation of DNA methylation factors?

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Support(s)

HRH Princess Caroline of Hanover, who through the Princess Grace Foundation, already supports medical research and anything that helps to relieve the sick children in France and around the world, has agreed to commit to our side so that our Center of Molecular medicine continues to meet the current challenges and fight diseases, and in particular the ones affecting children.

Legal mentions

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